Hepatocellular carcinoma (HCC) remains one of the most lethal and prevalent cancers worldwide. Systemic toxicity, drug resistance, high costs, and poor bioavailability often limit conventional therapies. As an alternative, natural bioactive compounds obtained from plants have increased attention due to their structural diversity, low toxicity, and ability to modulate multiple oncogenic pathways. The Mexican semi-desert host a wide variety of plant species traditionally used in herbal medicine, including Agave lechuguilla, Jatropha dioica, and Larrea tridentata, which are rich in different phytochemicals with documented anti-cancer activity. Nevertheless, the therapeutic potential of these bioactive compounds is hampered by poor solubility, chemical instability, and limited bioavailability. Pharmaceutical nanotechnology offers a promising solution through the development of nanosystems such as polymeric nanoparticles, liposomes, nanoemulsions, and nanogels, among others, that enhances drug delivery, improve cellular uptake, and enable targeted release. This review explores the current challenges in HCC treatment, summarizes the anti-cancer properties of selected Mexican semi-desert plants, and discusses the role of nanotechnology in optimizing the delivery of their bioactive compounds. By integrating traditional knowledge with modern nanomedicine, this work highlights a novel, sustainable approach aligned with global health priorities and the United Nations Sustainable Development Goals (SDGs), offering a pathway toward more effective and accessible cancer therapies.